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Role of biological agents in immune-mediated inflammatory diseases.

Abstract: A new era in the treatment of immune-mediated inflammatory disorders has begun with the clinical availability of anticytokine therapy. Biological agents that are currently available include 3 agents that decrease the activity of tumor necrosis factor-[alpha] (infliximab, adalimumab, etanercept) and an interleukin-1 receptor antagonist (anakinra), with many more in development. Those extraordinarily effective medications are an important addition to our therapeutic armamentarium, and, although originally developed for rheumatoid arthritis and Crohn disease, have been found to be efficacious in the treatment of seronegative spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis) and juvenile rheumatoid arthritis. Their role is currently being defined in other autoimmune disorders such as uveitis, sarcoidosis, interstitial lung disease, vasculitis, inflammatory myopathies, graft-versus-host disease, and Sjogren syndrome.

Key Words: biological therapy, IL-1 receptor antagonist, psoriatic arthritis, rheumatoid arthritis, TNF-[alpha] inhibitors

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Immune-mediated inflammatory disease (IMID) is a relatively new term used to collectively describe a group of clinically dissimilar conditions that share common inflammatory pathways. This dysregulation of the immune system has the potential to cause significant damage to the host, resulting in organ damage and increased morbidity and mortality rates. The underlying cause of these disorders is not known, and although seemingly very different, there are certain commonalities that suggest a stronger relation than currently understood. (1) For example, there is a genetic component, with positive family histories and twin concordance studies. This genetic susceptibility encompasses the entire spectrum of autoimmune diseases, and is not uncommon for different IMIDs to exist with increased frequency in the same family. Many of these diseases have similar environmental precipitants and cofactors (eg, stress, trauma, infectious agents) and share common cytokine pathways resulting in the propagation of chronic inflammation. Furthermore, most of these diseases respond to treatment with corticosteroids and immunosuppressive agents, and patients with multiple organ systems affected or coexistent diseases respond to systemic treatment given initially for one condition only. This experience strengthens the belief that these diseases are linked and the concept that "All inflammation is one."

The new millennium brings with it exciting developments in the treatment of immune-mediated inflammatory diseases. Basic research in cytokine expression and signaling has identified two key players in the pathophysiology of rheumatoid arthritis (RA): tumor necrosis factor (TNF)-[alpha] and interleukin (IL)-1. (2) Both cytokines have been found to be elevated in the serum, synovium, and synovial fluid of patients with RA. (3-5) Moreover, TNF-[alpha] and IL-1 are capable of inducing and augmenting joint damage in experimental models of arthritis. (3, 6-8) These findings led to the development of strategies to block their effects. This specific targeting by biological agents has only become possible with the recent advances in biopharmaceutical discovery and manufacturing; it began with the elucidation of monoclonal antibodies (mAb) and continued with the synthesis of soluble receptor fusion proteins and other elegant constructs. (9)

Tumor Necrosis Factor-[alpha] as a Mediator of Inflammatory Disease

It was 1893 when the observation was made that spontaneous or induced streptococcal infection can lead to reduction in the bulk of a malignant tumor. (10) We now think that this is due to infection-induced release of cytotoxic cytokines such as TNF-[alpha], (11) that is, a product of host defense and not an action of the organisms themselves. TNF-[alpha] was purified in the 1980s, and since then, many more biological and immune functions have been described beyond the induction of cachexia and tumor lysis that led to its discovery and naming. (11)

TNF-[alpha] plays a pivotal role in the host's defense. By maintaining local inflammation, it helps to seal off infections and keep them under control. It does so by inducing the synthesis of other inflammatory mediators such as prostaglandins, leukotrienes, platelet-activating factor, nitric oxide, and reactive oxygen species. It activates the vascular endothelium locally, causing vasodilation and increased permeability. Vascular endothelium adhesion molecules (ICAM-1, VCAM-1, E-selectin) and MHC class II are upregulated and recruitment of proinflammatory cells, immunoglobulins, and complement ensues. Platelets get activated and become "stickier," resulting in small vessel occlusion, and thus containment of the infection, which may also explain the previously mentioned tumor necrosis effect. (12) TNF-[alpha] also has a potent paracrine function, inducing (via a NF-[kappa]B-mediated mechanism) the secretion of pro-inflammatory cytokines such as IL-1, IL-6, and GM-CSF. (2) It also stimulates the production of various chemokines, including RANTES, IL-8, MCP-1, and MIP-1[alpha]. Finally, TNF-[alpha] plays a role in angiogenesis, which is critical to the growth and propagation of the rheumatoid synovium. (9)

TNF-[alpha] is synthesized by T-lymphocytes, B cells, synoviocytes, fibroblasts, and macrophages initially as a 26kD protein, which is later cleaved by TNF-[alpha]--converting enzyme (a serine metalloproteinase of the ADAMS family) into a monomeric 17-kD molecule. Three of these molecules form, under physiologic conditions, a noncovalently bound, cone-shaped homotrimer that cross-links membrane bound receptors that exist in 2 isoforms: TNF receptor I (TNFRI, p55) and TNF receptor II (TNFRII, p75). (2, 11, 13)

IL-1 plays an important role in the pathophysiology of joint destruction in rheumatoid arthritis

IL-1 is a key mediator of bone resorption and cartilage destruction in RA. (3, 14) The IL-1 gene family includes IL-1[alpha], IL-1[beta], and IL-1 receptor antagonist (IL-1ra). IL-1[alpha] and IL-1[beta] are both agonists secreted mainly by activated monocytes and macrophages and bind two separate receptors: type I (signaling receptor) and type II ("decoy" or "scavenging" receptor). Only when IL-1 binds to type I receptor is intracellular signal transmitted, which eventually results in metalloproteinase release as well as osteoclast activation and bone resorption. (2, 3, 15, 16)

The third member of the family, IL 1-ra, is a naturally occurring antagonist, also produced by macrophages, that binds with high affinity to type I receptor without triggering the signaling mechanism. Therefore, IL 1-ra blocks the binding of IL-1 and type I receptor (IL-1RI). IL 1-ra is found in increased concentrations in the synovial fluid of rheumatoid patients, but probably not high enough to suppress inflammation. (2, 17) Interestingly, in a classic set of experiments, blocking TNF-[alpha] downregulated IL-1 bioactivity almost completely. (18)

TNF-blocking Agents

Infliximab (Remicade)

Infliximab was the first anti-TNF-[alpha] agent to be used for the treatment of RA (19) and is also used in the treatment of Crohn disease. It is a chimeric (25% mouse FAB and 75% Ig human) mAb that binds to soluble and transmembrane TNF-[alpha] but not lymphotoxin-[alpha] (otherwise known as TNF-[beta]). The mouse portion contains a variable region binding site, whereas the human portion is responsible for effector functions.

It has been shown to lyse in vitro cells expressing TNF-[alpha] on the surface through complement-mediated and antibody-dependent, cell-mediated cytotoxicity. (20) It is unclear what the in vivo implication of this observation is, especially in terms of safety. One study demonstrated sustained decrease of peripheral monocytes (potentially expressing surface TNF-[alpha]) in the periphery of rheumatoid patients after the infusion of 10 mg/kg of infliximab. (21)

Infliximab is given as an intravenous infusion and has a terminal half-life of 8 to 9.5 days. After the initial infusion, repeat infusions are administered at 2 weeks, 6 weeks, and thereafter every 8 weeks. The usual starting dose is 3 mg/kg and can increase afterward up to a maximum of 10 mg/kg. The usual dose for Crohn disease is 5 mg/kg. (22) The half-life may become shorter if human anti-chimeric antibodies (HACA) develop with repeated infusions. (23) The frequency of HACA responses is inversely related to the dose of the infused mAb and diminishes with concurrent weekly oral methotrexate use (7% in combination therapy versus 21% with 3 mg/kg of infliximab alone). (23) As a result, infliximab has been approved for use in combination with weekly methotrexate. Other combinations with concomitant immunosuppressives such as leflunomide, azathioprine, mycophenolate mofetil may be as effective but have not been formally tested. (24) Not all patients achieve an optimal response at the low dosage (3 mg/kg) or the every-8-weeks maintenance schedule. (25) Data from the Swedish registry STURE suggest that as many as 45% of patients receiving infliximab require a dosage escalation over time, (26) and the percentage was even higher (75%) in a recent US study. (27) Another strategy used, often in conjunction with the dose escalation, is the shortening of the interval between infusions to 4 weeks. Both strategies, while being effective and well tolerated, can cause a proportionate increase in cost that often burdens the individual patient. Infliximab is administered as a slow infusion (2 hours) that should be further prolonged if there is a history of mild infusion reactions. As there is a potential for serious hypersensitivity reactions, a physician, appropriate medications, and emergency equipment should always be available. It cannot be used in persons with allergies to murine proteins and has not yet been approved for pediatric use. (24)

Infliximab in rheumatoid arthritis

The efficacy of infliximab in the treatment of RA has been well documented in many clinical trials. The first trial was conducted in 1992 in the United Kingdom and was designed to evaluate safety in 20 patients. (19) Patients with RA who were included had severe, long-standing disease and had been unresponsive to multiple disease-modifying anti-rheumatic drugs (DMARDs). They received a large dose of the mAb (20 mg/kg) over 2 weeks in 2 to 4 infusions that they tolerated well. Although not primarily designed to test efficacy, most patients reported almost immediate alleviation of pain and within days, amelioration of morning stiffness, fatigue, joint tenderness, and swelling. A reduction of swollen and tender joints was apparent after 2 and 4 weeks. (19, 28) Notable was the concomitant reduction in C-reactive protein (CRP) and serum IL-6.

The efficacy of infliximab was confirmed in a multicenter, randomized, double-blinded, placebo-controlled trial involving 73 rheumatoid patients who were randomly assigned to single infusions of placebo, low-dose mAb (1 mg/kg), and high-dose mAb (10 mg/kg). At 4 weeks' follow-up, only 8% of placebo-infused patients met the response criteria, in sharp contrast to 44% of the low group and 79% of the high group. Moreover, 60% reduction in pain, swollen and tender joints, and CRP was observed in the high-dose group, for a mean duration of response of 8 weeks versus 3 weeks in the low-dose group. (29) Once infliximab was validated as an important therapeutic option, the question that needed to be answered was whether it could safely be administered in a repeated fashion over a prolonged period of time without loss of efficacy. This question was initially addressed by a multicenter, multidose, randomized, double-blinded, placebo-controlled trial carried out in 101 patients with RA. (23) Unlike the previous trials, patients who were previously treated with low doses of methotrexate (MTX) were allowed to participate. Five infusions of placebo or infliximab (1, 3, or 10 mg/kg), with or without concomitant MTX (7.5 mg/wk), were administered over a period of 14 weeks. As monotherapy, infliximab was clearly effective at doses of 3 or 10 mg/kg, with a suggestive dose effect. In that dose range, 60% of patients met the response criteria (American College of Rheumatology 20% response rate [ACR20]) and benefit was maintained for about 16 weeks, in contrast with the 1 mg/kg group that had short-lived relief and subsequently became resistant to repeated infusions. In all three infliximab groups treated concomitantly with MTX, 60 to 80% of patients achieved Paulus 20 responses that in the 2 higher infliximab dose groups were sustained after cessation of therapy (week 14) until the last follow-up (26 weeks). The conclusion was that HACA generation is reduced by MTX cotreatment or by infusion of higher doses when infliximab is used as monotherapy.

The next step was a well-designed phase III, randomized, multicenter, double-blinded, placebo-controlled trial of infliximab in patients with active disease despite MTX treatment (ATTRACT). (30, 31) In the ATTRACT study, investigators enrolled 428 patients with active disease despite treatment with relatively high doses of MTX (median dose, 15 mg/wk). In this study, the optimal infliximab dose (3 versus 10 mg/kg) and the optimal dosing interval (4 versus 8 weeks) required for maintenance were both evaluated. The study population had long-standing RA, as evidenced by a mean duration of disease ranging from 9 to 12 years. (32) All patients were maintained on MTX, and the control group received MTX + placebo infusions. The primary end point, ACR20 response at 30 weeks, was met by 50% of patients who received MTX + 3 mg/kg infliximab and in 20% of patients who received MTX alone. All infliximab doses were efficacious, and a dose-response effect was apparent. Significantly more patients in the infliximab arm achieved ACR50 (26 to 31% vs 5%) or ACR70 (8 to 18% vs 0%). Important conclusions came from the rigorous radiologic analysis that used modified Sharp scores, which is a composite score measuring erosions and joint narrowing at hands and feet. At baseline, all treatment groups had moderately severe joint damage, with Sharp scores 67 to 82. One year of follow-up showed a marked reduction in the progression of the erosions and joint narrowing in the infliximab + MTX treatment groups when compared with MTX alone. All combination treatment groups showed significant retardation of radiologic progression after 1 year, with mean sharp score increase of 0.55 U versus 6.9U in the MTX only group. Notable was the fact that this prevention of subchondral bone and cartilage injury seemed to be independent of the anti-inflammatory properties of the drug, as it was present in both ACR20 responders and non-responders.

Recently, important results from the ASPIRE trial were published. In this multicenter, phase III, double-blinded, placebo-controlled trial involving 1,049 patients, the efficacy and safety of infliximab in combination with MTX versus MTX alone in the treatment of early RA was assessed. (33) Patients had been diagnosed with RA an average of 7 months earlier, but they already had radiologic evidence of erosions. They were randomly assigned to receive either MTX + infliximab (3 or 6 mg/kg) or MTX + placebo infusions. After 1 year of follow-up, all primary and major secondary end points were met. There was almost no radiographic progression with mean increases of 0.51 U (3 mg/kg group) and 0.46 U (6 mg/kg group) versus 3.7 U in the MTX group. Seventy-six percent of patients in the combination arm had significant reduction in disability as measured by the health assessment questionnaire (HAQ) versus 65% in the MTX-only group. There was greater improvement in all ACR scores in the patients treated with infliximab plus MTX, with 33 to 37% of patients achieving ACR70 compared with 21% of those in the MTX + placebo arm. This study confirmed the need for early and aggressive therapy of RA and provided evidence of the existence of a therapeutic window early in the natural course of the disease, when aggressive treatment can avert joint destruction. (34)

Infliximab in seronegative spondyloarthropathies

The spondyloarthropathies comprise ankylosing spondylitis, reactive arthritis, inflammatory bowel disease-associated arthritis, psoriatic arthritis, and undifferentiated forms. (35) There is clinical evidence that TNF-[alpha] plays a role, as it was found to be highly expressed in serum, synovium, and inflamed sacroiliac joints. (36)

In ankylosing spondylitis (AS), the efficacy of infliximab was demonstrated in several open pilot studies (37-40) and confirmed in a randomized, double-blinded, placebo-controlled trial (41) where infliximab treatment resulted in decreased disease activity and improved function at both the axial and peripheral joints as early as 2 weeks after the first infusion. Those results were corroborated by the largest so far multicenter, randomized, double-blinded, placebo-controlled trial of infliximab in AS that included 70 eligible patients with AS. (42) Half of these patients were assigned to infliximab therapy with 5 mg/kg (administered at weeks 0, 2, 6) and were compared with placebo infusions done under the same schedule. No DMARDs or corticosteroids were permitted. At 12 weeks, 53% of the patients in the active treatment arm achieved the primary outcome, which was a 50% improvement of disease activity (BASDAI), compared with only 8% in the placebo group. Taken together, these data strongly suggest a major breakthrough in the short-term treatment of severe AS. (43)

In psoriasis and psoriatic arthritis, infliximab was found effective initially in small, open-label studies (36, 44, 45) in reducing the symptoms and signs of the inflammatory synovitis and the skin disease. The preliminary results of a randomized, multicenter, double-blinded, placebo-controlled trial (IMPACT), so far reported in abstract form (33, 46) supported these studies. A total of 102 patients were randomly assigned to infliximab (5 mg/kg) or placebo (at weeks 0, 2, 6, 14), with an open-label extension in which infliximab was infused every 8 weeks until week 50. At 16 weeks' follow-up, 69% of the infliximab group had achieved ACR20 versus 8% in the placebo group. After switching to active treatment at week 16, a similar response was observed and the ACR20 increased to 72% by week 50. The effect on the skin was significant and sustained. (33, 46) Previously, infliximab had also been found to be effective in the treatment of moderate to severe plaque psoriasis in a small, double-blinded, controlled trial comparing 2 doses of infliximab (5 and 10 mg/kg) with placebo. (47) In the 5 mg/kg and 10 mg/kg groups, 82% and 73%, respectively, reached the clinically meaningful Psoriasis Activity and Severity Index (PASI), a 75% improvement compared with 18% of control subjects.

Infliximab in other inflammatory diseases

Infliximab has been used in the treatment of other systemic inflammatory diseases, including uveitis, inflammatory myopathies, sarcoidosis, adult-onset Still disease, graft-versus-host disease, Sjogren syndrome, and various vasculitides, including Behcet disease, refractory giant cell arteritis, and Wegener granulomatosis. (48)

Etanercept (Enbrel)

Etanercept is a fully human, soluble fusion protein created by the linkage of two ligand-binding regions of the p75 TNF-[alpha] receptor and the Fc portion of human IgG1. This fusion creates a molecule with a longer biological half-life (72 to 96 hours) than the parental native p75 (7 to 8 hours), allowing for intermittent subcutaneous dosing. It is dosed 25 mg SC twice weekly (BIW) in adults and in children 0.4 mg/kg (maximum, 25 mg/dose) BIW. The elimination half-life of etanercept is 115 hours, compared with 210 hours of infliximab. Other differences between those two medications are that etanercept also binds lymphotoxin-[alpha] (otherwise known as TNF-[beta]) and that unlike infliximab, does not lyse cells expressing transmembrane TNF in the presence or absence of complement. Etanercept is approved as monotherapy and does not have to be coadministered with MTX, although it frequently is coadministered with MTX in clinical practice.

Etanercept in rheumatoid arthritis

Etanercept was first evaluated as monotherapy in a phase II, randomized, dose-ranging, double-blinded, placebo-controlled trial. It involved 180 patients with refractory RA who were randomly assigned at dosages of either 0.25, 2, or 16 mg/[m.sup.2] given subcutaneously twice weekly for 3 months. A dose-dependent reduction in disease activity was seen, with 75% of the high-dose group attaining ACR20s, compared with 14% in the placebo group. (49) Etanercept therapy was associated with significant reduction in acute-phase reactants such as ESR and CRP. Most patients exhibited a rapid response to therapy and reported significant improvement as early as 1 month after initiation of therapy. Cessation of therapy was associated with relapse of disease and return to the pretrial level of disease activity. (20, 28, 49)

Results were supported by a subsequent phase III, 6-month, randomized, double-blinded, placebo-controlled trial comparing 2 doses of etanercept (10 and 25 mg SC BIW). (50) Both doses were more effective than placebo, and the 25 mg dose was more effective than the 10 mg dose. At 6 months, 59% of the patients in the high-dose group achieved ACR20 response, versus 11% of placebo-treated patients.

The next step was to evaluate the combination of etanercept and MTX in a 6-month, randomized, double-blinded, placebo-controlled trial of 89 patients. (51) All patients were already taking MTX (mean dose, 18 mg/wk) and were randomly assigned to MTX + etanercept 25 mg SC BIW (59 patients) and MTX + placebo injections (30 patients). At the end of 6 months, 71% of the patients in the combination group demonstrated ACR20 and 39% ACR50 responses, compared with 27% (ACR20) and 3% (ACR50) in the MTX-only group. There was no comparison at that time of the combination therapy to etanercept alone, so it was not possible to ascertain from this study whether the enhanced response represented an additive or a synergistic benefit. Nevertheless, the conclusion from that study was clear in that treatment of established RA with the combination of etanercept is safe, well tolerated, and more effective than MTX alone.

In recent years, the concept that RA represents a medical urgency and that early referral and treatment with DMARDs is essential to decrease the radiologic progression and increase the remission rate has gained wide acceptance. (25, 34, 52) The ERA (Early Rheumatoid Arthritis) trial (53) compared 2 doses of etanercept (10 and 25 mg SC BIW) with 20 mg/wk MTX in patients diagnosed with early RA (<3 years since diagnosis). This was a 52-week, randomized, double-blinded, placebo-controlled trial with 632 patients. The 25 mg dose group at 1 year showed slower increase of the Sharp score than the group that received MTX (0.47 versus 1.03 U) as a result of decreased progression of erosions. Although not seen at the end of the first 52 weeks, a significantly higher percentage of etanercept-treated patients achieved higher ACR20 scores (72 vs 59%, P = 0.005) after the completion of the 2-year open-label follow-up study. (54) Five-year follow-up results were reported in the 2003 ACR meeting, and the patients who were continuously treated with etanercept, both in the randomized study and during the open-label extension, had a sustained response in the signs and symptoms of the disease. At 5 years, 68% achieved ACR20, 49% ACR50, and 33% ACR70 and had decreases in the individual components of the ACR response, including inflammation markers. More importantly, there was radiographic evidence of sustained arrest of disease progression, as measured by the modified Sharp score. Specifically, during the randomized trial (0 to 2 years), the mean increase of the Sharp score was 0.59 U/yr and overall mean increase (0 to 5 years) was 0.57 U/yr. In comparison, patients randomly assigned to MTX had initially higher rates of radiographic progression (mean Sharp score increase: 0.99 U/yr) that decreased after the addition of etanercept (0.35 U/yr, years 2 to 4) and (0.22 U/yr, years 4 to 5), and at 5 years, the mean increase was similar to the etanercept continuously treated group (0.56 U/yr). Another secondary outcome that the investigators looked at was corticosteroid use in the etanercept-only group: of the 74 remaining patients treated with corticosteroids at the beginning of the study, 50% at the end of the first year and 73% at the end of year 4 had decreased or discontinued corticosteroid usage. (55)

Recently, the preliminary results of the TEMPO trial were reported in abstract form. A multicenter, randomized, double-blinded, placebo-controlled trial of 686 patients with RA more than 1 year was designed to compare the efficacy and tolerability of etanercept alone (25 mg SC BIW + placebo) with MTX alone (mean dose, 17 mg/wk + placebo injections) or combination of the two medications. Patients had to have inadequate response to DMARD therapy (other than MTX) and could not be taking MTX at the beginning of the study. The primary end points were ACR responses and the 52-week change in the modified Sharp score. The combination therapy significantly prevented x-ray progression and produced significantly higher ACR scores than either agent alone. (56) This was the first time that a TNF inhibitor in combination with MTX has shown to be superior to monotherapy with either MTX or the TNF inhibitor (etanercept) alone and strongly argues for early combination therapy and against the practice of decreasing the dose of MTX after initiation of anti-TNF therapy. The TEMPO trial data are also in sync with the recent trend for early and aggressive treatment of RA to avert joint destruction. This notion of a therapeutic window early in the course of RA was also reinforced by the previously described ASPIRE trial, in which infliximab was used.

Etanercept in the treatment of spondyloarthropathies

In AS, efficacy of etanercept was suggested in a 6-month open label study (57) and convincingly demonstrated in a randomized, double-blinded, placebo-controlled study that followed 40 patients over 4 months with a 6-month open-label extension. (58) After the initial 4 months, 80% of etanercept-treated patients (25 mg SC BIW) had achieved the primary outcome measurement (defined as at least 20% improvement in 3 of 5 measures) ASAS-20 compared with 30% of placebo (P = 0.004). During the open-label extension, patients who had previously been in the placebo group and were subsequently treated with etanercept showed dramatic improvement, comparable with the active group. The therapeutic effect of etanercept was supported by a 6-month European phase III trial. (59) In a 6-month, randomized, multicenter, double-blinded, placebo-controlled trial, 277 patients with AS were randomly assigned to 25 mg etanercept SC or placebo twice per week. The primary objective (ASAS-20) was achieved at 6 months by 57% of patients in the etanercept group and 22% of patients in the placebo group. The therapeutic response was seen early in the trial, with 59% of the etanercept group patients versus 28% in the placebo group reaching ASAS-20 response. (60) Reports of safety and efficacy of etanercept have also emerged, in abstract forms, in the treatment of juvenile AS and reactive and undifferentiated spondyloarthropathies. (36)

In psoriasis and psoriatic arthritis, the first single-center, double-blinded, placebo-controlled study in 60 patients found that after 3 months, significantly more patients treated with etanercept (73%) achieved ACR20 response than the patients treated with placebo (13%). (61) The etanercept group also had significant skin improvement, as measured by 75% improvement in the PASI composite score (21 vs 0%). These positive results were further confirmed by a larger (205 patients), multicenter, placebo-controlled trial. Again at 3 months, 59% of etanercept-treated patients and 15% of placebo-treated patients achieved ACR20 response and similarly had clinically meaningful skin improvement (47 vs 0%). Of importance is that this dramatic difference was seen despite background MTX use. (36,61-67) Radiographic comparison data from the above study, using a modified Sharp score, were presented in abstract form during the 2002 ACR annual session: At 6 months and 1 year (open label) of follow-up, there was significantly less radiographic progression in the etanercept group compared with placebo. Patients receiving etanercept subcutaneous injections had a mean change in joint erosion score of -0.08 U/yr, whereas those taking placebo (but still taking MTX) had a mean change of +0.69 U/yr (P < 0.0001). In the 2003 ACR meeting, the authors reported the 1-year results of the open-label extension that 169 (81 taking placebo and 88 taking etanercept) of the initial 205 patients could enroll after the completion of the 24-week blinded study. The patients who were originally taking etanercept and continued the medication to a maximum of 106 weeks (mean, 80 weeks) showed sustained improvement in both the joint and skin disease. The patients who were switched from placebo to etanercept (with a mean duration of treatment of 45 weeks) showed similar improvement once given etanercept. Those two groups combined, after 48 weeks of anti-TNF treatment, tolerated the medicine well, and after 48 weeks of treatment, 66% achieved ACR20, 47% ACR50, and 16% ACR70. The positive effect was also seen in individual components of the ACR response (26 and 28% had no swollen and tender joints, respectively) and in reduction of disability (38% had an HAQ score of 0). Similar response was seen in psoriasis improvement. Also at 48 weeks, 57% had clearing (or near clearing) of psoriatic target lesions, and of patients with generalized disease evaluated by the PASI score, 38% achieved a clinically significant PASI-75 response. (68)

Those results further supported the important role of anti-TNF treatment in the management of psoriasis and psoriatic arthritis and demonstrated sustained skin and joint response, for up to 108 weeks, in etanercept-treated patients. Another trial confirmed the beneficial effect of etanercept in skin psoriasis and also suggested that higher doses of etanercept (such as 50 mg SC BIW) not currently being used in the treatment of RA or psoriatic arthritis may be more efficacious. (69)

Etanercept in other inflammatory diseases

Etanercept has been used in the treatment of Behcet disease, inflammatory muscle disease, multicentric reticulohistiocytosis, adult-onset Still disease, and graft-versus-host disease. A multicenter study (WGET) is underway to evaluate its role in Wegener granulomatosis.

Adalimumab (Humira)

Adalimumab, previously known as D2E7, is a fully human anti-TNF monoclonal antibody. The antibody binds specifically TNF-[alpha], without binding lymphotoxin, and blocks the interaction with the p55 and p75 receptors. It has been shown in vitro to lyse cells expressing TNF on their surface in the presence of complement. It is administered subcutaneously every week or every other week, with an estimated half-life of 6 to 13.7 days. It can be used as monotherapy or in conjunction with MTX for the treatment of RA.

A phase I, randomized, double-blinded, placebo-controlled trial of a single intravenous dose of the medication showed that the medication was safe and rapidly efficacious. (70) A phase II study of subcutaneous adalimumab at doses of 20, 40, and 80 mg was carried out in 283 patients. After 3 months, 49, 57, and 56% of patients in those groups (and 10% in the placebo group) reached ACR20 response. (71) The ARMADA was a randomized, 24-week, multicenter, double-blinded, placebo-controlled trial, during which 271 patients with active RA, despite concomitant therapy with MTX, were randomly assigned to 20, 40, or 80 mg of adalimumab every other week or placebo. At 6 months, the combination (adalimumab + MTX) group had significantly higher proportions of patients achieving ACR20 responses at all doses (47.8, 67.2, and 65.8%, respectively). Responses were rapid and seen as early as 1 week after treatment. (72) A year-long study (73) of 619 patients with RA with active disease despite MTX showed that adalimumab given subcutaneously weekly (20 mg) or every other week (40 mg) with concomitant MTX significantly inhibited radiographic progression and structural joint damage and improved signs and symptoms of RA, when compared with placebo. Recently, the 5-year results of an open-label, follow-up study were reported in the 2003 ACR; patients were originally enrolled in a double-blinded trial of adalimumab plus MTX versus placebo plus MTX (stable dose, mean = 16 mg/wk).

Of the initial 54 patients, 53 (98%) entered the extension phase and 36 (68%) remained on therapy for 5 years. Improvements in tender joint count (TJC) and swollen joint count (SJC) were sustained for 5 years. At the last visit 25% of patients had 0 tender joints and 25% had 0 swollen joints. Notably, the rate of adverse events did not differ during the 5-year extension period from the rate reported in the shorter-term, randomized, controlled trials. (74) In another open-label extension study of adalimumab as monotherapy, sustained efficacy was demonstrated into year 5 in patients with active RA, as measured by ACR20-50 to 70, TJC and SJC, and HAQ Disability Score. The safety profile observed in the open-label period was comparable to the placebo-controlled period. Adalimumab was well tolerated, with 76% of patients remaining on therapy in this analysis. (75)

The SONORA (Study of New-Onset Rheumatoid Arthritis) is a prospective, 5-year, multicenter inception cohort study of patients with new-onset RA designed to evaluate treatment patterns as well as clinical and health-related outcomes in early RA. It included 1,011 patients with recently diagnosed RA (>3 and <12 mo) and at their annual visits data are collected regarding clinical disease activity, quality of life (HAQ, SF-36), laboratory values (CRP), work status, drug therapy, and radiographic progression. In addition, patients report quarterly disease status via questionnaires. At 1 year, data from 632 patients with early RA in SONORA have been analyzed, with MTX being the most commonly used DMARD (65% of patients) and only 12% of patients receiving TNF antagonist therapy, usually in combination with MTX. The ACR responses in this cohort of patients with early RA treated primarily with traditional DMARDs were modest compared with results from clinical studies with anti-TNF agents. (76) Two studies were presented in 2003, where patients from the DE019 trial were divided into two subsets, based on duration of disease at entry. In patients with disease duration of [less than or equal to]2 years (early disease), adalimumab treatment provided greater improvements in clinical outcomes, as measured by the HAQ disability index score, ACR20, 50, 70 score, and the SJC. The authors concluded that early, aggressive treatment of RA with TNF antagonist therapy provides opportunities to achieve greater improvement in clinical outcomes. (77,78) Currently, there are studies underway to evaluate efficacy of adalimumab in ankylosing spondylitis, psoriasis, and psoriatic arthritis.

Anakinra (Kineret)

Presently, the only IL-1 blocker marketed and approved for use in RA, alone or in conjunction with MTX, is the recombinant form of human IL-1-ra (Anakinra). In Europe, this agent has been approved for the treatment of RA only in combination with MTX. This biological agent binds both soluble and cell-surface IL-1 receptors, competitively inhibiting IL-1 from binding to its receptor and initiating a signaling cascade. It was developed on the basis that production of endogenous IL-ra by synovial macrophages in RA joints is relatively deficient and hence incapable of controlling proinflammatory responses. The drug is administered as a 100 mg SC daily injection, based on its terminal half-life of 4 to 6 hours. However, in vitro observations indicate that anakinra is required in 100-fold excess of IL-1 to achieve 50% reduction in IL-1--dependent biological actions and that may be clinically challenging. (14-16,79) Anakinra is well tolerated, with injection site reactions being the most common side effects, occurring in up to 70% of patients in a dose-dependent manner. (80) Those reactions do not require treatment and can diminish with continued use. (81) The incidence of serious infections is also increased, and the agent should be discontinued in the face of an active infection. (82,83)

Regarding efficacy, five randomized, placebo-controlled studies have been conducted with a total of 2,932 patients with RA. In the European Monotherapy Study, a 6-month, multicenter, randomized, double-blinded, placebo-controlled trial, therapeutic effect was seen as early as 2 weeks after the initiation of treatment. At 6 months, 43% of the 116 patients in the 150 mg SC daily regimen achieved ACR20 response, in contrast to 27% of the 121 patients in the placebo group. The clinical improvement in the 75 and 30 mg SC daily groups did not reach statistical significance. (80) When patients continued to receive anakinra for an additional period of 6 months, responses were maintained. The same trial demonstrated significant retardation of the radiographic progression of the disease: 347 (74%) of the 472 patients had serial hand radiographs at weeks 0 and 24 that were analyzed by the Larsen method. There was a 41% reduction in the radiographic joint damage in the anakinra group when they compared the calculated Larsen scores. (80,84) This retardation of joint destruction may also be explained by the fact that IL-1 blockade inhibits osteoclast function and thus prevents bone erosions.

The MTX combination therapy study (85) evaluated 419 RA patients with inadequate responses to MTX. This was also a 6-month, multicenter, randomized, double-blinded, placebo-controlled trial using various doses of SC anakinra. At the end of 6 months, 46% of the patients in the 1 mg/kg group and 38% in the 2 mg/kg group achieved ACR 20 response, significantly higher than placebo (19%). (85) A large, international, multicenter, placebo-controlled trial with 1,414 patients confirmed safety but highlighted the slightly increased incidence of serious infections. (82)

Initially, there was increased interest in combining anticytokine therapy and simultaneously neutralizing the two key pro-inflammatory cytokines in RA, IL-1, and TNF-[alpha]. The first study to examine this hypothesis was a 24-week. multicenter, open-label, single-arm study, aimed to evaluate the safety of anakinra administered daily by subcutaneous injections, in patients with RA on background etanercept. Etanercept was maintained at 25 mg BIW and anakinra was administered at 1.0 mg/kg per day. The sample size (n = 58) was not based on formal statistical considerations. There was a 7% (4/58) serious infection rate for the combination group, which at the time did not seem markedly different when compared with either drug alone. (86)

The next study (87) was a multicenter, double-blinded, 24-week study in which subjects (n = 242) with RA using methotrexate but naive to biological agents were randomly assigned to the following 3 groups:

* Etanercept 25 mg twice/wk and anakinra 100 mg daily (full-dose etanercept and anakinra)

* Etanercept 25 mg once/wk and anakinra 100 mg daily (half-dose etanercept and anakinra)

* Placebo daily plus etanercept 25 mg twice/wk (etanercept alone)

The primary end point was efficacy, as measured by the ACR50 response at 24 weeks, and apparently there was no increased benefit with the combination therapy versus etanercept alone.

The incidence of serious adverse events was higher in the etanercept and anakinra combination arms than in the etanercept-alone arm: 2.5% in the etanercept-alone arm; 4.9% in the half-dose etanercept and full-dose anakinra arm; 14.8% in the full-dose etanercept and anakinra arm.

The incidence of serious infectious events was higher in the etanercept and anakinra combination arms than in the etanercept-alone arm: 0% in the etanercept-alone arm; 3.7% in the half-dose etanercept and full-dose anakinra arm; 7.4% in the full-dose etanercept and anakinra arm.

There was one death in the etanercept BIW + anakinra daily group (approximately 5 months before initiation of study therapy). The patient had acute respiratory failure secondary to pneumonia and pulmonary fibrosis. (87) Based on the above results, combination therapy (etanercept + anakinra) cannot be recommended at the present time, and a warning has been included in the anakinra product insert. (88)

Upcoming Biological Agents for the Treatment of Autoimmune Diseases

Although the available TNF-[alpha]-blocking agents (and to a lesser extent, anakinra) provide effective control of RA in most cases, approximately one third of the patients enrolled in the clinical trials that evaluated those agents failed to meet ACR20 response criteria. Therefore, new means of reducing TNF activity are being developed and new targets for biological agents are currently being evaluated. (48) Early human trials of a pegylated soluble TNF-[alpha] receptor type 1 are under way, after it was shown to be effective in an animal model in reducing signs of synovitis and in suppressing pro-inflammatory cytokines TNF-[alpha], IFN-[gamma], IL-2, and IL-17. (89) A very attractive target is TNF-[alpha]--converting enzyme (TACE), which cleaves cell surface--bound TNF-[alpha] to release soluble cytokine. Another molecule in development is CDP 870, which is an anti-TNF-[alpha] antibody fragment (Fab) that was pegylated to prolong its plasma half-life and is currently undergoing human trials.

New monoclonal antibodies that target pro-inflammatory cytokines and chemokines are being developed and tested in RA trials, including anti-IL-6 mAb, anti-IL-12 mAb, anti-IL-18 mAb, and anti-C5a mAb. Very promising has been the application of anti-CD20 mAb (Rituximab), an agent used widely in hematology/oncology for the treatment of non-Hodgkin lymphoma, and phase II/III trials are underway.

CTLA4-Ig belongs to a new class of therapeutic agents known as costimulation blockers. Unlike current biological therapies that target single cytokines, those novel drugs act earlier in the inflammatory sequence of events and inhibit the activation of T cells by blocking the "second signal" necessary for optimal activation. They may also have a direct inhibitory effect on dendritic cells and macrophages. (90) CTLA4-Ig binds to both CD80 and CD86 on the surface of antigen-presenting cells and blocks their binding to the T cell CD28, thereby inhibiting costimulation. A 6-month, randomized, multicenter, double-blinded, placebo-controlled trial of CTLA4-Ig in RA resistant to treatment with MTX demonstrated dose-related improvement in the signs, symptoms, and physical function of patients with the disease. (91) Specifically, patients treated with 10 mg/kg of CTLA4-Ig were more likely to have ACR20 response (60%) than patients receiving placebo infusions (35%) and were also more likely to have a significant improvement in physical function, as measured by the SF-36 survey. (91)

A humanized mAb (efalizumab) that disrupts the costimulatory T cell LFA-1-ICAM-1 interaction has been developed for the treatment of psoriasis and is currently being tried in RA in conjunction with MTX. Alefacept (human LFA-3/Ig[G.sub.1] fusion protein), a novel biological agent used also in psoriasis, binds to the CD2 receptor on T cells, thereby selectively depleting CD45RO + memory-effector T cells. Some preliminary data on its use in RA have recently emerged, suggesting that addition of alefacept to MTX is superior to placebo and efficacy correlates with reduction of memory T cells in the periphery. (92) Furthermore, our growing understanding of intracellular signaling mechanisms has led to development of small molecules that inhibit key signaling peptides and thus have the potential to block the generation of several key cytokines simultaneously. (20) Of particular importance appears to be p38 MAP kinase, and several molecules are being developed. Syk kinase is part of the signaling cascade that is initiated after activation of the Fc[gamma] and Fc[epsilon] receptors in macrophages and mast cells, respectively, and syk inhibitors have been found to be effective in animal models of arthritis. (93-95) Patients with autoimmune diseases such as systemic lupus erythematosus, myasthenia gravis, Wegener granulomatosis, and RA have elevated levels of soluble B-lymphocyte stimulator (BLyS), which regulates B-cell survival, proliferation, and antibody production. LymphoStat-B, a fully human monoclonal antibody that inhibits soluble BlyS, has recently undergone a phase I trial in patients with systemic lupus erythmatosus. (96)

Safety

TNF-[alpha], by facilitating cell-to-cell communication, plays a critical role in the regulation of inflammation and containment of infections. There is growing evidence that TNF inhibition is associated with serious infections, and clearly an impairment of the host to fight pathogenic microorganisms, from Gram-positive and Gram-negative bacteria to less common pathogens causing opportunistic infections. Of particular concern are multiple reports of reactivation of Mycobacterium tuberculosis latent infections. After multiple reported TB cases appeared in the medical literature worldwide, 70 cases of TB infection after infliximab infusion, one of which was in the ATTRACT study, were reported to the FDA in June 2001. Of these patients, 12 died, and at least 4 of the deaths were attributed to TB. In etanercept-treated patients, 25 cases were reported after marketing, with 1 death, as of 2002. The median time to onset of TB was longer at 46 weeks, in comparison to 12 weeks with infliximab and 30 weeks with adalimumab. Among 2,468 adalimumab-treated patients, 13 cases of TB were reported, of which 7 occurred early in the clinical trials. There seems to be a particular pattern in the presentation of TB associated with TNF inhibition: It occurs early in the therapeutic course, it is frequently disseminated, and the majority of patients have extrapulmonary disease. In lieu of these safety concerns, many experts recommend vigilant monitoring for the development of TB while on anti-TNF therapy and preventive measures. Tuberculin testing before initiation of anti-TNF treatment, with a cutoff of 5 mm of induration after 48 to 72 hours, should be performed, and, if positive, prophylactic treatment with isoniazid (INH) (300 mg daily + vitB6 50 mg daily if at risk for peripheral neuropathies) should be initiated and coadministered with the agent. The above recommendation is only valid if the chest radiograph excludes active TB. A question that often arises in this setting is how a positive tuberculin test should be interpreted when there is a history of BCG vaccination: Currently, experts recommend identical treatment, as if the vaccination had never occurred. That is because BCG reactivity tends to wane over time, it is often difficult to distinguish BCG effects versus latent TB infection, and, if active infection is left untreated, mistaken for BCG reaction, it can become life-threatening in the face of TNF inhibition. (97) More intensive prophylactic regimens should be considered in areas of high INH resistance. (98)

Table 1 summarizes the most current worldwide experience with anti-TNF agents and M tuberculosis infection in patients with RA. (99)

Serious bacterial infections have been reported, most of them after marketing, including at least 2 fatal cases of pneumococcal sepsis and necrotizing fasciitis and multiple cases of listeriosis (mostly associated with infliximab therapy), of which two thirds were fatal. In addition, severe systemic fungal infections have been reported, involving Aspergillus fumigatus, Histoplasma capsulatum, Coccidioides immitis, Cryptococcus neoformans, and Pneumocystis carinii, which resulted in most cases in the death of the immunocompromised host. Anakinra has also been associated with increased risk of serious infections in the clinical trials (2.1% in the anakinra group vs 0.4% in the placebo group) and should not be administered if there is an active infection. So far, it has not been associated with increased risk of TB and opportunistic infections. However, its concurrent use with TNF blockers is contraindicated because it increases the incidence of side effects (particularly infections) without additional benefit. (82,83)

The TNF inhibitors have also been associated with other rare but very serious adverse events that were in the majority reported after their approval. These were episodes of demyelinating disease (particularly with etanercept), hepatotoxicity, aplastic anemia and pancytopenia, intestinal perforation, and a lupus-like syndrome with positive serologies that subsided after the discontinuation of the anti-TNF agent.

Another unexpected toxicity was the increase in mortality rate in patients with congestive heart failure (CHF) treated with TNF inhibitors. Animal model and preliminary human data had suggested that TNF might contribute to the CHF pathogenesis. However, 2 large, randomized, placebo-controlled trials with etanercept (RENAISSANCE and RECOVER) involving patients with New York Heart Association (NYHA) class 2 and 3 CHF were terminated early, as the groups treated with etanercept failed to show significant benefit. The one randomized, controlled trial with infliximab (ATTACH), that involved 150 NYHA class 3 and 4 (severe) CHF patients was also terminated early, but this time because of increased hospitalizations (21.6%) and deaths (5.9%) in the infliximab arm (10 mg/kg) compared with placebo (10.2% hospitalizations and no deaths). Therefore, treatment with TNF blockers is contraindicated in patients with RA and concurrent severe CHF. (100)

Despite multiple reports of neoplasia (especially lymphoma) associated with use of TNF blockers, the March 2003 FDA meeting that was specifically convened to update these safety concerns, concluded that RA patients have a 2- to 3-fold increase in relative risk (SIR) for lymphoma. Although RA patients on TNF inhibitors have a 2.3 to 6.3 SIR in clinical trials that is higher that the general population, this increased risk approximates the relative risk from having RA. Careful long-term follow-up is needed and may give us more answers. (100)

Cost

Across the board, the estimated yearly cost to use a biological agent is in the proximity of 13,000 US dollars. However, the cost has to be balanced against the significant economic impact RA and the other IMIDs pose to the individual patient and society as a whole. Rheumatoid arthritis patients have 3 times the direct medical costs, twice the hospitalization rate, and 10 times the work disability rate of an age- and sex-matched population. A recent study showed annual medical costs for a RA patient to be approximately $8,500, with indirect costs related to disability and work loss being 3 times higher. (101) Therefore, if the new medications can arrest uncontrolled inflammation and prevent its catastrophic consequences causing significant morbidity, disability, and deterioration of the quality of life, then the use of a biological agent can be a cost-effective decision. (52)

Conclusion

The introduction of the biological agents and especially the TNF inhibitors has revolutionized the therapy of RA, ankylosing spondylitis, psoriatic arthritis and psoriasis, and Crohn disease. The list keeps getting longer as clinicians use these medications off-label for the treatment of other inflammatory diseases and experience accumulates. Concerns about cost and access to those medicines need to be resolved. Although generally thought to be safe, these potent medicines have been associated with rare but very serious side effects, and many of them were reported after marketing; long-term safety data are still missing. The establishment of long-term registries for careful monitoring of side effects (especially infections, lymphoproliferative diseases, and induction of new autoimmunity) has been advocated to this effect.

While those medicines represent a tremendous advancement in the understanding and treatment of autoimmune disorders, they are clearly not a panacea. They do not cure the disease and there are patients that demonstrate a complete lack of efficacy, raising the issue of poorly understood, now TNF-independent processes. Another explanation would be genetic variability and the presence of TNF/TNF receptor polymorphisms. Such knowledge would be extremely helpful, as it could predict clinical failures.

Other issues that need to be solved by careful clinical trials are the place of these wonder medicines in our therapeutic algorithm. Should they replace traditional DMARDs as first-line therapy or should they

be part of a step-up approach and be reserved for DMARD failures? Another approach advocated by experts in the field is early aggressive therapy of mild or moderate disease using combination of DMARDs or DMARD/biological agents until there is no evidence of disease and then possibly gradual withdrawing of agents. Another key question is whether to use the biological agents alone or in combination with DMARDs, and, if so, the optimal combination that still has to be determined. Many experts think that we are still at the embryonic stage of biological treatments and that the real breakthrough will be targeted therapy of specific pro-inflammatory cytokines and/or chemokines that are responsible for the disease manifestations and may weigh differently in individual patients. Nevertheless, we have entered the exciting era of biologic agents and what we see now is just the beginning of a revolution in therapeutics that has given hope to millions of patients.
Table. Mycobacterium tuberculosis in patients with rheumatoid arthritis
treated with tumor necrosis factor antagonists

 Etanercept Infliximab Adalimumab*

Patients treated 150,000 200,000 2,500
Patient-years exposure 230,000 230,000 4,900
TB reports 38 172 13
Distribution: Use of agents
 USA 90% 64% 60%
 Outside USA 10% 36% 40%
Distribution: TB cases
 USA 20 (52%) 55 (32%) 3 (23%)
 Outside USA 18 (48%) 117 (68%) 10 (67%)
Time to onset of TB 1-22 mo 75% by 6 3-8 mo
 (median. wk: 97%
 11.2) by 7 mo
Extrapulmonary/miliary
 involvement 50% 45% 40%

Data through 4th quarter 2002.
* All data for adalimumab are from clinical trials.
From Cavanaugh A. Cush JJ, HOTLINE 2003 2http://www.rheumatology.org/
research/hotline/0803chf.asp) (99)


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RELATED ARTICLE: Key Points

* The treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and other immune-mediated inflammatory disorders has been revolutionized by the introduction of the biological agents.

* Tumor necrosis factor-<ga>--blocking and interleukin-1--blocking agents can efficiently eliminate symptoms, prevent structural damage, and greatly improve the patient's quality of life.

* Close monitoring by experienced physicians is warranted, as these medications have been associated with rare but serious side effects.

* The high cost of these agents must be balanced against the direct and indirect costs that rheumatoid arthritis and its effects have on the individual patient and society.

Petros Efthimiou, MD, and Joseph A. Markenson, MD

From the Hospital for Special Surgery, Weill Medieal College of Cornell University, New York, New York.

Reprint requests to Dr. Petros Efthimiou, Weill Medical College of Cornell University, New York, NY 10021. Email: pee2001@med.cornell.edu
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Title Annotation:Featured CME Topic: Arthritis
Author:Markenson, Joseph A.
Publication:Southern Medical Journal
Date:Feb 1, 2005
Words:11376
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